What is the best approach to manage a man with hyperandrogenism (high free testosterone), low Sex Hormone-Binding Globulin (SHBG), and hypotestosteronemia (low total testosterone)?

Management of High Free Testosterone, Low SHBG, and Low Total Testosterone

The priority is to identify and treat the underlying cause of low SHBG—most commonly obesity, insulin resistance, metabolic syndrome, or type 2 diabetes—through aggressive weight loss and metabolic optimization, NOT testosterone replacement therapy. 1

Understanding the Paradox

This clinical presentation represents a functional hypogonadism where the biochemical picture is misleading:

• Low SHBG is typically caused by obesity, insulin resistance, metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease, or nephrotic syndrome 1
• When SHBG is low, total testosterone appears falsely low while free testosterone (the bioactive fraction) may be normal or even elevated 2, 3
• The "high free testosterone" indicates this patient is NOT truly hypogonadal at the tissue level 2

Diagnostic Algorithm

Step 1: Confirm the Laboratory Pattern

• Measure morning total testosterone (8-10 AM) on two separate occasions to confirm low total testosterone (<300 ng/dL) 4, 2
• Measure free testosterone by equilibrium dialysis (gold standard) to confirm it is truly elevated 4, 2
• Measure SHBG, LH, and FSH to characterize the pattern 4, 2

Step 2: Identify the Cause of Low SHBG

Screen systematically for conditions that lower SHBG 1:

• Metabolic causes (most common):

  • Calculate BMI and waist circumference 1
  • Screen for metabolic syndrome components (hypertension, dyslipidemia, hyperglycemia) 1
  • Check fasting glucose, HbA1c, and insulin resistance markers 1
  • Evaluate for nonalcoholic fatty liver disease with liver function tests 1

• Endocrine causes:

  • Check TSH to rule out hypothyroidism 1
  • Consider screening for Cushing's disease or acromegaly if clinical features present 1

• Medication review:

  • Identify use of growth hormone, glucocorticoids, or anabolic steroids 1

Step 3: Assess for True Hypogonadal Symptoms

Evaluate whether the patient has specific symptoms of testosterone deficiency 1, 4:

• Sexual symptoms: Reduced libido, erectile dysfunction, decreased spontaneous/morning erections 1
• Physical symptoms: Decreased vigorous activity, hot flushes 1
• Psychological symptoms: Low mood, decreased motivation, fatigue 1

Critical caveat: If free testosterone is truly elevated, these symptoms are NOT due to testosterone deficiency and should prompt evaluation for other causes 2

Treatment Approach

Primary Intervention: Lifestyle Modification

Weight loss is the cornerstone intervention for this clinical scenario 2:

• Weight loss reduces aromatization of testosterone to estradiol, which improves the negative feedback loop on pituitary LH secretion 2
• Weight loss improves insulin resistance, which directly increases SHBG production 2
• Expected benefits include improvements in fasting glucose, insulin resistance, triglycerides, HDL cholesterol, lean body mass, and waist circumference 2

What NOT to Do: Testosterone Replacement Therapy

Testosterone replacement therapy is absolutely contraindicated in this patient 4:

• The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men (those with normal free testosterone), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 4
• Exogenous testosterone will suppress spermatogenesis and cause infertility 4
• Testosterone therapy will not address the underlying metabolic dysfunction causing low SHBG 2
• The patient's elevated free testosterone indicates adequate tissue-level androgen activity 2

Additional Metabolic Management

• Treat insulin resistance with metformin if indicated 1
• Manage components of metabolic syndrome (hypertension, dyslipidemia) per standard guidelines 1
• Encourage regular physical activity and exercise 4
• Address nonalcoholic fatty liver disease if present 1

Common Pitfalls to Avoid

1. Do not treat based on total testosterone alone when SHBG is low—this leads to inappropriate testosterone therapy in men who are not truly hypogonadal 2

2. Do not use screening questionnaires alone to diagnose hypogonadism, as they lack specificity 1, 4

3. Do not assume symptoms are due to testosterone deficiency when free testosterone is normal or elevated—investigate other causes 4, 2

4. Do not prescribe testosterone to men seeking fertility—it will cause severe oligospermia or azoospermia 4, 2

Follow-Up Monitoring

After initiating weight loss and metabolic interventions:

• Recheck total testosterone, free testosterone, and SHBG at 3-6 months to assess response 4, 2
• Monitor metabolic parameters (glucose, lipids, liver enzymes) 1
• Reassess symptoms to determine if they improve with metabolic optimization 4

Only if free testosterone becomes frankly low on repeat testing after addressing metabolic factors should testosterone replacement be considered 4, 2